The cyclodextrins, CDs, as know as the cyclic oligosaccharides, have six to eight glucose unites linked by the α-1,4-glucosidic bonds, where CDs are usually nonhygroscopic and crystalline materials. The molecule of CDs is also distinguished for having a cylinder-shape, a macro ring structure and a large internal axial cavity. Contrary to the character of hydrophobic on the internal cavity of CDs, the outer surface thereof is hydrophilic. It is found that CDs are able to form the inclusion complexes with many drugs due to the possession of its cavity by either the whole or partial drug molecule. With the aim of improving pharmaceutical interest, such as the solubility in aqueous media, the dissolution rate, the chemical stability and the bioavailability, the application of complexation in different drugs with CDs has been extensively studied in the recent years.
Although the inclusion complex made with CDs can improve the dissolution rate of many insoluble drugs, the safety aspects of CDs for the various routes of administration are not yet completely clarified. Several issues are discussed as following: for cellular interactions, CDs could induce shape changes of cellular membrane invagination on the human erythrocytes and even cause lysis under a high concentration rate of CDs. As to the parenteral safety issue, it is found that CDs could induce the nephrotoxicity and some hepatic disorders. Due to lacking of absorption through the gastrointestinal tract, all toxicity studies of orally administered CDs were shown as practically nontoxic. Nevertheless, the inhibition of mammalian amylases by β-CD potentially turns the digestible starches into materials that can not be digested and causes an increased incidence of soft stools and diarrhea. In the ophthalmic use of CDs, the increase in solubility and/or stability could avoid the irritation and discomfort of drug; however, high concentration of CDs could have an opposite effect of irritating the conjunctival and corneal surface and causing the reflex tearing and blinking. Some reports indicated that nasal preparation with CDs could cause the hemolytic activity of the nasal mucous membrane or ciliotoxicity. When using CDs as rectal absorption enhancers, the irritating effects of CDs on the rectal mucosa and the potential for systemic absorption of the pathogenic substances need to be considered, because it might cause severe irritation with erosion of the rectal mucosa. Finally, CDs may have some interactions with some components of the skin, which may reduce the function of skin as a barrier and contribute in part to the enhancement of drug absorption.
Nanospheres are solid colloidal particles with the size thereof being range between 10 to 1000 nm that have been employed to ameliorate the solubility and the dissolution rates for the water insoluble drugs. It has known that reducing the size of drug particle can increase its particle surface area, and can also improve its solubility and dissolution rate. Different techniques have been used to manufacture nanosized drug particles, such as dry and wet milling and solvent-based techniques, such as the emulsification-solvent evaporation, the emulsification-solvent diffusion and the precipitation solvent evaporation. As one of new alternative device for drug manufacturing, nanospheres have been used for parenteral injection and oral administration. For clinical application, nanospheres are reported being not only to increase the therapeutic efficiency of drug but also to reduce the quantity of drug administrated and to minimize undesirable side effects.
Gliclazide, 1-(1-azabicyclo(3,3,0)octyl)-3-(p-tolylsulfonylurea), which is termed GL hereafter, as a second generation sulfonylurea, is widely used in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Because of its short-term acting, GL has been considered suitable for diabetic patients with renal impairment and for elderly patients that have reduced renal function and follow a sulphonylureas treatment which may increase the risk of hypoglycemia. The molecule of GL or the GL solid complex represent the following characters as low solubility in gastric fluids, low dissolution rate and inter-individual variability in its bioavailability.
Based on the above, to develop a new GL nanosphere and a manufacturing method therefor has become a major subject in this art, wherein the GL nanosphere not only increases the solubility and dissolution rate for GL, but also takes considerations to the various dosage forms for GL.
In order to overcome the drawbacks of the GLs or the GL solid complexes in the prior art, the novel GL nanosphere with increased solubility, enhanced dissolution rate, safety, and being free from the undesirable side effects derived from the carrier or excipient, the manufacturing method therefor and the application thereof are provided. The particular design in the present invention not only solves the problems described above, but also is easy to be implemented. Thus, the invention has the utility for the industry.